Synthesis of oxindoles from anilines and β-thio carboxylic esters or amides

ABSTRACT

Preparing oxindoles and intermediates therefor by reacting an N-haloaniline with β-thio esters or β-thio amides to form an azasulfonium halide, reacting the azasulfonium halide with a base to form an ortho-[thio-ether (hydrocarbonoxycarbonyl) alkyl]aniline, or a [thio-ether (aminocarbonyl) alkyl]aniline, reacting the orthosubstituted aniline with an acid to form a 3-thio-ether-2-oxindole, and then reducing the 3-thio-ether-2-oxindole with Raney Nickel to form the 2-oxindole.

The invention described herein was made in the course of work under agrant or award from the United States Department of Health, Educationand Welfare.

This is a division of application Ser. No. 355,207, filed Apr. 27, 1973,now U.S. Pat. No. 3,897,451.

FIELD OF THE INVENTION

This invention relates to processes for making oxindoles and tointermediate compounds for use in such processes. More particularly,this invention provides an improved process -making oxindoles and somenew intermediate compounds which can be used to prepare oxindoles.

Oxindoles have been used as intermediates in the preparation of variousindole alkaloids. For detailed discussions of the presently-knownmethods of oxindole synthesis see The Chemistry of Indoles, by R. J.Sundberg, Academic Press, New York (1970).

The details of a stereospecific method for the orthoalkylation ofaromatic amines was published in Tetrahedron Letters, 497 (1972). Thatprocedure involved the addition of dialkylsulfides to themono-N-chlorinated amine to give an azasulfonium salt, followed by ylidformation, and intramolecular attack of the ylid at the ortho position.In that way an aniline could be converted to a 2-alkylthioalkylanilinein good to excellent yield. Raney Nickel desulfurization then producedthe 2-alkylaniline.

Other prior art that might be considered pertinent is the following: a)P. Claus and W. Vycudilik, Monatsh. Chem., 101, 396 (1970), whereinClaus et al. reacted an aniline with a dimethylsulfoxide to form asulfilimine, not an azasulfonium salt; and b) P. Claus, W. Vycudilik,and W. Rieder, Monatsh. Chem., 102, 1571 (1971), wherein thesesulfilimine compounds are thermally rearranged tohydrocarbon-S-hydrocarbon aromatic amine thio-ethers. Other papers whichcan be considered include a publication by Prof. C. R. Johnson et al.,Tetrahedron Letters, No. 6, pp. 501-504 (1972), and "Indoles" Part I, byR. K. Brown, W. J. Houlihan, Ed., Wiley Interscience, New York (1972).In addition, the paper of U. Lerch and J. G. Moffatt entitled"Carbodiimide-Sulfoxide Reactions. XIII. Reactions of Amines andHydrazine Derivatives" in the Journal of Organic Chemistry, Vol. 36,3861 (1971) may be considered as pertinent as the Claus publications,supra.

However, none of that recent prior art discloses the hereindescribedmethod for preparing oxindoles. There is a need in the art for makingoxindoles which are used as intermediates in making a wide variety ofindole related products, many of which have significant physiologicalproperties.

SUMMARY OF THE INVENTION

Briefly, it has been discovered that oxindoles can be prepared byreacting an N-haloaniline with a β-thio carboxylicester or amide undermild, substantially anhydrous conditions, in a solvent sufficientlypolar to dissolve the reactants, to form an azasulfonium halide salt,and thereafter treating the azasulfonium salt with a base to form anortho-[1-(thio-ether)-(hydrocarbonoxycarbonyl)alkyl]aniline or anortho-[1-(thio-ether)-(aminocarbonyl)alkyl]aniline, which are believedto be new compounds, treating the ortho-substituted aniline with an acidto form a 3-thio-ether-2-oxindole compound. Thereafter, if desired, the3-thio-ether-2-oxindole can be reduced, e.g., with Raney Nickel, toremove the thio-ether group and to form the 2-oxindole compound. Thisprocess can be conducted through its several steps up to the isolationof the 3-thio-ether-2-oxindole compound in one reaction vessel, withoutseparation of the intermediate reaction products. However, theazasulfonium halide and the new ortho-substituted aniline compounds canbe recovered and at least partially purified before continuing theprocess, if desired.

OBJECTS OF THE INVENTION

It is an object of the invention to provide an improved process formaking 2-oxindoles using primary and secondary aromatic amines andβ-thio carboxylic esters or β-thio-carboxylic amides as startingmaterials for the process.

It is another object of this invention to provide a process for making2-oxindoles which enables a less tedious synthesis and the use of morereadily available, less expensive, reactant chemicals under mildreaction conditions, and which process now permits the use of anilinestarting materials containing substituents which otherwise could not beused.

It is also an object of this invention to provide some newortho-substituted aniline compounds which find particular usefulness ina process for making 2-oxindoles therefrom.

Other objects, aspects, and advantages of the invention will becomeapparent to those skilled in the art from the specification and theclaims which follow.

DETAILED DESCRIPTION OF THE INVENTION

According to the process of this invention, a primary or secondaryaniline is first reacted with a source of positive halogen to preparethe N-haloaniline. Many sources of positive halogen are known and can beused to form the N-haloaniline. Examples of positive halogen sources forthis reaction include tert.-butyl hypochlorite, N-chlorosuccinimide,calcium hypochlorite, sodium hypochlorite, sodium hypobromite, and thelike. The N-chloroanilines are preferred for reasons of availability ofreactants to make them and cost of materials, but other positive halogencompounds can be used to make useful N-haloanilines for use in thisprocess.

The essential features of the process comprise:

a. reacting under substantially anhydrous conditions in an organicliquid diluent sufficiently polar to keep at least a portion of thereactants in solution at a temperature ranging from the Dry-Ice/Acetonemixture temperatures (about -78°C.) to about 10°C., preferably below0°C., an N-haloaniline of the formula ##STR1## wherein R is hydrogen, ahydrocarbon radical free from aliphatic unsaturation containing from 1to 8 carbon atoms.

A denotes chlorine or bromine, but is preferably chlorine;

each of Y and Z is hydrogen or is a substituent which does not donateelectrons more strongly than a methoxyl group in the meta position, andnot more than one of Y and Z, as a substituent, is ortho to the --N(R)Agroup position on the ring;

the --N(R)A group position having at least one ring carbon atom orthothereto in an unsubstituted state;

with β-thio carboxylic ester or a β-thio carboxylic amide compoundhaving a formula selected from the group consisting of ##STR2## whereinR¹ is lower alkyl, phenyl or benzyl;

R² is hydrogen, lower alkyl, phenyl or benzyl;

R³ is lower alkyl, phenyl or benzyl;

each R⁴ is hydrogen or lower alkyl, or the two R⁴ groups are takentogether with the nitrogen to form a ring containing from 4 to 5methylene carbon atoms and up to one ring oxygen atom, for a timesufficient to form an azasulfonium salt having a formula selected fromthe group consisting of ##STR3## wherein Y, Z, R, R¹, R², R³, each R⁴and A are as defined above;

b. reacting the azasulfonium salt of formula IV or V with asubstantially anhydrous base, preferably one whose conjugate acid has apKa greater than about 6, to effect rearrangement of the azasulfoniumsalt and to form an ortho-substituted aniline having a formula selectedfrom the group consisting of ##STR4## wherein Y, Z, R, R¹, R², R³, andeach R⁴ are as defined above;

c. either heating the ortho-substituted aniline compound of formula VIor VII to a temperature of from about 50°C. to about 150°C., or reactingthe aniline with an acid, preferably an economical mineral acid such asaqueous hydrochloric acid, sulfuric acid, phosphoric acid or the like,to effect formation of a 3-thio-ether-2-oxindole compound of the formula##SPC1##

wherein Y, Z, R, R¹, and R² are as defined above; and, if desired,

d. treating the 3-thio-ether-2-oxindole compound of the formula VIIIwith a desulfurizing reducing agent, e.g., with Raney Nickel, or itsequivalent, to form a compound having the formula ##SPC2##

wherein Y, Z, R, and R² are as defined above.

In the preferred embodiments for practicing the process, that is, thepreferred choice of anilines for use in the process, are those wherein Ris hydrogen or lower alkyl, A is chlorine, each of Y and Z is hydrogenor a halogen, nitro, cyano, lower alkyl, lower alkyloxy, lower acyloxy,a carbonyloxy-lower alkyl or a carbonyloxy-phenyl group. The preferredβ-thio carboxylic ester compounds (II) for use in the process are thosewherein R¹ is lower alkyl, R² is hydrogen or lower alkyl, R³ is loweralkyl. If the β-thio carboxylic amide compound (III) is used, thepreferred ones are those wherein R¹ is lower alkyl, R² is hydrogen orlower alkyl, each R⁴ is hydrogen or lower alkyl.

The new compounds provided by this invention can be described as havinga formula selected from the group consisting of ##STR5## wherein R ishydrogen, a hydrocarbon radical free of aliphatic unsaturation andcontaining from 1 to 8 carbon atoms;

R¹ is lower alkyl, phenyl or benzyl;

R² is hydrogen, lower alkyl, phenyl or benzyl;

R³ is lower alkyl, phenyl or benzyl;

each R⁴ is hydrogen, lower alkyl, or the two R⁴ groups are takentogether with the nitrogen to complete a ring containing 4 to 5methylene carbon atoms and up to 1 ring oxygen atom;

each of Y and Z is hydrogen or a substituent selected from the groupconsisting of halogen, nitro, cyano, lower alkyl, lower alkyloxy, loweracyloxy, a carbonyloxy-lower alkyl and carbonyloxy-phenyl groups.

Preferred compounds of the above formulas (A) and (B) are those whereinR is hydrogen or lower alkyl, R¹ is lower alkyl, R² is hydrogen or loweralkyl, R³ is lower alkyl, and each R⁴ is hydrogen or lower alkyl.

Examples of the new compounds prepared according to the inventioninclude:

2-[(methylthio)(methoxycarbonyl) methyl]aniline;

2-[1-(isopropylthio)-1-(ethoxycarbonyl)ethyl]-4-chloro aniline;

2-[1-(phenylthio)-1-(benzyloxycarbonyl)butyl]-3-nitroaniline;

2-[α-(ethylthio)-α-(butoxycarbonyl)benzyl]-3,4-dichloroaniline;

2-[(benzylthio)(phenoxycarbonyl)methyl]-4-cyanoaniline;

2-[(methylthio)(hexyloxycarbonyl)methyl]-4-methylaniline;

2-[1-(pentylthio)-1-(ethoxycarbonyl)-2-phenethyl]-3-methoxyaniline;

2-[(methylthio)(phenoxycarbonyl)methyl]-4-acetoxyaniline;

2-[1-(ethylthio)-1-(ethoxycarbonyl)ethyl]-3-ethoxycarbonylaniline;

2-[(methylthio)(propyloxycarbonyl)methyl]-3-bromoaniline;

2-[(ethylthio)(ethoxycarbonyl)methyl]-4-fluoroaniline;

2-[(methylthio)(N,N-dimethylaminocarbonyl)methyl]aniline;

2-[1-(methylthio)-1-(aminocarbonyl)ethyl]-3,4-dichloroaniline;

2-[(ethylthio)(N-ethylaminocarbonyl)methyl]-3-nitroaniline;

2-[1-(phenylthio)-1-(N,N-dibutylaminocarbonyl)ethyl]-4-methylaniline;

2-[(methylthio)(ethoxycarbonyl)methyl]-N-methylaniline;

2-[(ethylthio)(aminocarbonyl)methyl]-N-phenylaniline;

2-[1-(ethylthio)-1-(N,N-dimethylaminocarbonyl)propyl]-N-benzylaniline;

2-[α-(methylthio)-α-(piperidinocarbonyl)benzyl]-N-cyclohexylaniline;

2-[α-(phenylthio)-α-(1-morpholinocarbonyl)benzyl]-N-propylaniline;

2-[(benzylthio)(1-pyrrolidinocarbonyl)methyl]-N-ethylaniline, and thelike.

As used herein, the term "lower alkyl" means a C₁ to C₆ -alkyl radical,e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl,n-pentyl, neopentyl, n-hexyl, and the like. The term "lower alkoxy"denotes a C₁ to C₆ alkyl-O-- group wherein the C₁ to C₆ -alkyl is asexemplified above. The term "lower acyloxy" denotes formyloxy and a C₁to C₆ -alkyl-C(O)O-- group wherein the C₁ to C₆ -alkyl is as exemplifiedabove. The term "lower alkanoyl" denotes formyl and a C₁ to C₆-alkyl-C(O)-- group.

The aniline compounds which can be used as starting materials in thisprocess are those which have a free, unsubstituted carbon position onthe aromatic ring ortho to the amino nitrogen group. Such compounds areknown or are obtainable by known procedures. Many of them are describedin publications such as "Chem Sources", Directories Publishing Co.,Flemington, N.J. 08822 (1972). The aniline may be unsubstituted or maycontain one or more substituents, preferably not more than twosubstituents on aromatic ring carbon atoms. The substituents should beatoms or groups which do not donate electrons more strongly than ameta-, methoxy group. Not more than one of such substituents should beortho to the --N(R)A group position. The --N(R)A group position of theaniline compound must have at least one ring carbon atom ortho theretoin the unsubstituted state. Examples of substituents which can be in thering include halogen (fluorine, chlorine, bromine, iodine), nitro,cyano, lower alkyl, lower alkyloxy, lower acyloxy, a carbonyloxy-loweralkyl, and carbonyloxy-phenyl groups. Examples of useful startingcompounds include aniline, chloroanilines such as 3-chloroaniline,4-chloroaniline, 3,4-dichloroaniline, 3-fluoroaniline, 4-fluoroaniline,3-bromoaniline, 4-bromoaniline, 4-iodoaniline, 3-nitroaniline,4-nitroaniline, 3-cyanoaniline, 4-cyanoaniline, the toluidines such as2-methylaniline, 3-methylaniline, 4-methylaniline, 4-ethylaniline,4-hexylaniline, 3-propylaniline, 3-chloro-4-methylaniline, the loweralkyloxy-substituted anilines such as 3-methoxyaniline,4-acetoxyaniline, 4-propionylaniline, 4-hexanoyloxyaniline, the 3- and4- -carbonyloxy-lower alkylanilines such as benzocaine(4-ethoxy-carbonylaniline), 4-methoxycarbonylaniline,3-propoxycarbonylaniline, as well as 3-phenoxycarbonylaniline,4-phenoxycarbonylaniline, and the like. Secondary anilines which may beused include those having a C₁ to C₈ -hydrocarbon group bonded to thamino nitrogen and include the N-C₁ to C₈ -alkylanilines such as theN-methyl, N-ethyl, N-butyl, N-tert.-butyl, N-octylanilines as well asthe N-phenyl, N-tolyl, N-xylylanilines and the N-cycloalkylanilines suchas N-cyclopropyl, N-cyclobutyl, N-cyclopentyl, N-cyclohexyl, andN-cyclooctylanilines, and such compounds substituted on ring carbonatoms thereof with halogen, nitro, cyano, lower alkyl, lower alkyloxy,lower acyloxy, a carbonyloxy-lower alkyl or a carbonyloxy-phenyl asexemplified above.

The β-thio carboxylic esters and amide compounds of formulas II and III,above, are exemplified by the lower alkyl, phenyl and benzyl esters ofα-loweralkylthio-, α-phenylthio and α-benzylthio lower alkanoic acids,phenylacetic acid, and phenylpropionic acids and the correspondingamides. Procedures for making such compounds are known in theliterature, e.g., in an article by E. Bullmann and K. A. Jensen, Bull.Chim. Soc., 5, 3, 2310 (1936), and in Chem. Abstracts, 52, p. 1265g(1958) by E. G. Howard. Examples of such starting materials include:

ethyl methylthioacetate

ethyl 2-methylthiopropionate

butyl 2-ethylthiobutyrate

phenyl 2-methylthio-2-phenylacetate

benzyl 2-benzylthiopropionate

methyl-2-phenylthioacetate

α-methylthioacetamide

α-ethylthiopropionamide

α-phenylthiobutyramide

α-benzylthioacetamide

2-propylthio-3-phenylpropionamide

α-methylthio-N,N-dimethylacetamide

α-ethylthio-N-methylpropionamide

α-methylthio-α-phenylacetamide

1-(α-methylthioacetyl)piperidine

1-(α-ethylthiopropionyl)morpholine

1-(α-methylthio-α-phenylacetyl)pyrrolidine, and the like.

The reactions of the process up to the point of base addition should beconducted in a liquid, substantially anhydrous medium which issufficiently polar to dissolve at least a portion of the N-haloanilineand the β-thiocarboxylic ester or amide reactants at relatively lowtemperatures, e.g., from the cooled temperatures obtained by immersingthe reaction vessel in a Dry Ice/Acetone mixture (about -78°C.) to about10°C., preferably below about 0°C., up to the point of base addition,although the reaction temperature becomes less critical after theazasulfonium salt is formed. When the base addition is completed, thereaction mixture need not be cooled, and the temperature of the mixturecan be allowed to rise to room temperature. The acid addition step canbe conducted at any convenient temperature, for example, at 0°C. to50°C.

The solvent used to dilute the reactants and to disperse the heat ofreaction should be a compound or mixture of compounds which is liquid atreaction temperatures and which is sufficiently polar to solubilize atleast a portion of the reactants. It can be, e.g., an alkyl halide suchas methylene chloride, ethylenedichloride, chloroform, carbontetrachloride, ethers such as diethyl ether, dipropyl ether,tetrahydrofuran, lower alkanols and alkylene glycols and glycol etherssuch as methanol, ethanol, ethylene glycol, butyl ether of ethyleneglycol, lower alkanonitriles such as acetonitrile, propionitrile,solvent mixtures containing the compounds of the above type, and thelike.

The azasulfonium halide salt and base treatment steps of the process areconducted under substantially anhydrous conditions; that is, areasonable degree of care is taken to avoid the introduction of waterinto the reaction mixture during these steps, although the introductionof small incidental amounts of water, introduced with solvents orreactants, is not substantially detrimental to the process.

The base which is reacted with the azasulfonium salt, IV or V, can beany base which will cause formation of an ylid intermediate, which willundergo a Sommelet-Hauser type of rearrangement, and effect hydrogentransfer to produce the ortho-substituted aniline of formula VI or VII.Bases which can be used for this purpose are those whose conjugate acidshave a pKa of greater than about 6 and include, for examaple, alkanolicalkali metal hydroxides such as methanolic sodium hydroxide, potassiumhydroxide, lithium hydroxide and calcium hydroxide, as well as sodiummethoxide, potassium methoxide, sodium and potassium ethoxides,potassium and sodium carbonates, and organic bases such as lower alkylamines such as ethylamine, diethylamine, triethylamine, tributylamine,and aromatic amines such as pyridine, the lutidines, and the like.

Treatment of the azasulfonium salt with the base results in rapidconversion of the azasulfonium salt through its unisolated intermediatesto the derivative having formula VI if a β-thio carboxylic esterreactant had been used, or to the formation of intermediates havingformula VII if the β-thio carboxylic amide had been used. Theintermediate products VI and VII can be isolated, if desired, but thisis not necessary. Both crude reaction mixtures containing compounds VIor VII can be treated with acid to form oxindole derivative of formulaVIII.

As an example, a typical procedure could involve treating the selectedaniline in methylene chloride solution at -65°C. with tert.-butylhypochlorite, to form the N-chloroaniline, followed by the addition ofthe β-thio carboxylic ester or amide at -65°C., to form the azasulfoniumsalt and then with triethylamine to obtain the ortho-substitutedaniline. These ortho-substituted anilines are thereafter treated withaqueous 2N hydrochloric acid to obtain the 3-methylthio-2-oxindole.These 3-thio-ether-2-oxindole products can be isolated and treated withRaney Nickel or equivalent reducing agents to remove the 3-thio-ethergroup and to form the 2-oxindole product of this process.

The new ortho-substituted aniline compounds having the chemicalstructures VI and VII above are useful as intermediates for preparingthe corresponding 3-thio-ether-2-oxindole compounds having the chemicalformula VIII, which in turn can be converted to 2-oxindole compoundshaving chemical formula IX above. Many of the 2-oxindoles which can beprepared by the new process of this invention are known usefulcompounds. The 2-oxindole products of the process of this invention canbe used as intermediates in the preparation of indole alkaloids, asindicated above. In addition, the 2-oxindole compounds produced by theprocess of this invention can be used as intermediates in processes forpreparing a wide variety of pharmaceutically useful compounds. Forexample, 2-oxindole compounds are used in the preparation of indolederivatives which are central nervous system depressants andanti-inflammatory drugs [Japanese Pat. No. 72-36,757 (1970); U.S. Pat.No. 3,686,210 (1972)]. Uses of 2-oxindoles in the synthesis of indolecompounds are published by S. Sakai, Yuki Gosei Kagaku Kyohai Shi, 30,434 (1972). In addition, 2-oxindoles of this invention can be used tomake 2-oxindole compositions which are useful as anti-diarrheal agents(U.S. Pat. No. 3,585,866), anti-bacterials, anti-inflammatory agents(Japanese Pat. No. 71-14,898) [German Offen. No. 1,956,237 (1971)];drugs useful in the treatment of arthritis [German Offen. No. 2,046,595(1971)], and the like.

The invention is further exemplified by the following detailed examplesand preparations which are given by way of illustration only.Temperatures recited herein are in degrees Centigrade unless otherwiseindicated.

The following general procedure was used for the synthesis of2-oxindoles from anilines and β-thio carboxylic esters and amides:

To a vigorously stirred solution of 0.044 mol of the aniline in 150 mlof methylene chloride at -65°C. was added dropwise a solution of 0.044mol of t-butylhypochlorite in 20 ml of the same solvent to form theN-chloroaniline. After 5-10 minutes, 0.044 mol of the β-sulfide ester oramide dissolved in 20 ml of methylene chloride was added causing anexotherm, and stirring at -65°C. was continued for 1 hour to form theazasulfonium salt. Usually the azasulfonium salt did not precipitate.Subsequently, 0.044 mol of triethylamine in 20 ml of methylene chloridewas added to form the ortho-substituted aniline. After the addition wascompleted the cooling bath was removed and the solution was allowed towarm to room temperature. A 50-ml portion of water was added and theorganic layer was separated and evaporated. The residue was redissolvedin 150 ml of ether and stirred overnight with 20 ml of 2N aqueoushydrogen chloride to form the 3-thioether-2-oxindole compound. Ingeneral, the 2-oxindole had precipitated and was collected byfiltration. A second fraction could be obtained from the ether layer byconcentrating it after it had been dried.

Desulfurization of the 3-methylthio-2-oxindoles was accomplished bystirring a solution of 0.5 to 2.0 g of the appropriate3-methylthio-2-oxindole in 50 ml of absolute ethanol with an excess ofRaney Nickel W-2 for 30 min. Filtration and evaporation gave a residuethat was redissolved in methylene chloride and dried. After filtrationthe solvent was removed leaving pure desulfurized 2-oxindoles in yieldsgenerally varying from 70-85%.

W-2 Raney Nickel Preparation for Use

The W-2 Raney Nickel used in these experiments was obtained from W. R.Grace & Company, Raney Catalyst Division, South Pittsburg, Tennessee, asNo. 28 Raney Active Nickel Catalyst in water. A portion of this wasplaced in a beaker and washed with distilled water until neutral to pHpaper and then several more times with distilled water, three times with95% ethanol, and three times with absolute ethanol. The catalyst underabsolute ethanol was stored in brown bottles until use.

EXAMPLE 1 PREPARATION OF 5-METHYL-2-OXINDOLE AND INTERMEDIATES THEREFOR

Following the above procedure p-toluidine was converted toN-chloro-p-toluidine. The N-chloro-p-toluidine was treated with ethylmethylthioacetate to form the azasulfonium salt, of general formula IVabove. The azasulfonium salt reaction mixture was then treated withtriethylamine to obtain the ortho[(methylthio)(ethoxycarbonyl)methyl]-p-toluidine. Treatment of thisortho-substituted-p-toluidine with hydrochloric acid, as described, gave2.88 g (0.015 mol, 34% yield) of 5-methyl-3-methylthioindole, m.p.136°-137°:

This compound (recr. from methanol); ir (KBr) 3350 (NH) and 1680cm.sup.⁻¹ (C=O): pmr (aceton-d₆) τ 0.78 (1H,s,NH), 2.80-3.30 (3H, m,aromatic H), 5.75 (1H, s, SCH), 7.72 and 7.94 (3H, s, CH₃ and SCH₃).

Anal. Calcd for C₁₀ H₁₁ NOS: C, 62.15; H, 5.74; N, 7.25; S, 16.59 Found:C, 61.85; H, 5.81; N, 7.14; S, 16.49.

Treatment of the 5-methyl-3-methylthio-2-oxindole with Raney Nickel, asdescribed, gave the 5-methyl-2-oxindole in 55% yield, m.p. 171.5°-174°(Lit. m.p. 168°C.)

EXAMPLE 2 PREPARATION OF 4-NITRO-2-OXINDOLES AND INTERMEDIATES THEREFOR

Following the described procedure m-nitroaniline is converted toN-chloro-m-nitroaniline. The N-chloro-m-nitroaniline reaction mixturewas treated with ethyl methylthioacetate to form the azasulfonium salt,having general formula IV. The azasulfonium reaction mixture is treatedwith triethylamine to form the ortho-[(methylthio)(ethoxycarbonyl)methyl]-m-nitroaniline. This ortho-substituted-m-nitroanilineintermediate is treated with hydrochloric acid to form 5.90 g (0.0268mol., 61% yield) the 3-methylthio-4-nitro-2-oxindole, m.p. 228°-230°C.

(recr. from methanol); ir (KBr) 3350 (NH) and 1700 cm.sup.⁻¹ (C=O), pmr(DMSO-d₆) τ 0.30 (1H,s,NH), 2.28-2.82 (3H, m, aromatic H), 5.28 (1H, s,SCH), 8.08 (3H, s, SCH₃).

Anal. Calcd for C₉ H₈ N₂ O₃ S: C, 48.21; H, 3.60; N, 12.49; S, 14.30.Found: C, 48.27; H, 3.65; N, 12,38; S, 14.19.

EXAMPLE 3 PREPARATION OF 7-METHYL-2-OXINDOLES AND INTERMEDIATES THEREFOR

Ortho-toluidine was converted to the N-chloro-ortho-toluidine by thedescribed procedure. This reaction mixture was treated with ethylmethylthioacetate to form the azasulfonium salt, having general formulaIV. The azasulfonium salt was treated with triethylamine to form the2-methyl-6-[(methylthio)(ethoxycarbonyl)methyl] aniline intermediate.This ortho-substituted aniline reaction mixture was treated withhydrochloric acid as described to obtain 5.65 g of the7-methyl-3-methylthio-2-oxindole, (0.0294 mol., 67% yield), m.p.194°-195°C.

(recr. from methanol); ir (KBr) 3350 (NH) and 1680 cm.sup.⁻¹ (C=O); pmr(DMSO-d₆) τ -0.42 (1H, s, NH), 2.80-3.30 (3H, m, aromatic H), 5.58 (1H,s, SCH), 7.82 and 8.02 (3H, s, CH₃ and SCH₃).

Anal. Calcd for C₁₀ H₁₁ NOS: C, 62.15; H, 5.74; N, 7.25; S, 16.59.Found: C, 61.90; H, 5.79; N, 7.17; S, 16.46.

Desulfurization of 1.0 g (5.2 mmol.) of the7-methyl-3-methylthio-2-oxindole with Raney Nickel, as described above,gave a 72% yield of 7-methyl-2-oxindole, m.p. 206°-207°C., (Lit.203°-204°C.).

EXAMPLE 4 PREPARATION OF 1-METHYL-2-OXINDOLE AND INTERMEDIATES THEREFOR

Following the above general procedure N-methylaniline was converted tothe N-methyl-N-chloroaniline. The N-methyl-N-chloroaniline reactionmixture was treated with ethyl methylthioacetate to form theazasulfonium salt, having general formula IV. The azasulfonium saltreaction mixture was treated with triethylamine to form the2-[(methylthio)(ethoxycarbonyl) methyl]-N-methylaniline. Thisortho-substituted aniline was treated with hydrochloric acid to give3.92 g (0.0203 mol., 46%, or 90% calculated on the unrecovered aniline)of 1-methyl-3-methylthio-2-oxindole, m.p. 87.5°-88.5°C. (recrystallizedfrom ether).

ir (KBr) 1680 cm.sup.⁻¹ (C=O); pmr (CCl₄) τ 2.60-3.50 (4H, m, aromaticH), 5.98 (1H, s, SCH), 6.88 and 7.88 (3H, s, NCH₃ resp. SCH₃).

Anal. Calcd for C₁₀ H₁₁ NOS: C, 62.15; H, 5.74; N, 7.25; S, 16.59.Found: C, 62.09; H, 5.71; N, 7.43; S, 16.57.

Desulfurization of 0.50 g (2.59 mmol.) of the1-methyl-3-methylthio-2-oxindole with Raney Nickel as described, gave a77% yield of 1-methyl-2-oxindole, m.p. 83°-84.5°C. (Lit. m. p.86°-88°C.).

EXAMPLE 5 PREPARATION OF 5-NITRO-2-OXINDOLE AND INTERMEDIATES THEREFOR

3-Methylthio-5-nitro-2-oxindole was obtained from p-nitroaniline andethyl methylthioacetate by the general procedure using dichloromethaneas a solvent. The nitroaniline (0.044 mol) was dissolved in 300 ml ofdichloromethane. This solution was subsequently cooled under vigorousstirring to -70°C. resulting in a suspension to which thet-butylhypochlorite (0.044 mol), dissolved in 10 ml dichloromethane, wasadded. After a 3-hour period of stirring, most of the nitroaniline haddissolved and a solution of the sulfide (0.044 mol) in 10 ml ofdichloromethane was added followed by an 8 hour period of stirring at-70°. From here on the procedure as described in the general procedurewas followed giving 4.92 g (0.024 mol, 51%) of product, m.p. 196°-197°(recr. from methanol); ir (KBr) 3200 (N--H) and 1700 cm.sup.⁻¹ (c=O);pmr (DMSO-d₆) τ -1.53 (1H, s, NH), 2.00 and 3.15 (1H, dd, J=8, aryl H),2.10 (1H, broad s, aryl H), 5.44 (1H, s, SCH) and 8.18 (3H, s, SCH₃).

Anal. Calcd for C₉ H₈ N₂ O₃ S: C, 48.21; H, 3.60; N, 12.49; S, 14.30.Found: C, 47.97; H, 3.75; N, 12.51; S, 14.17.

EXAMPLE 6 PREPARATION OF 3-METHYL-2-OXINDOLE AND INTERMEDIATES THEREFOR

Following the general procedure aniline was converted toN-chloroaniline. The N-chloroaniline reaction mixture was treated withethyl 2-methylthiopropionate to form the azasulfonium chloride salt,having general formula IV. The azasulfonium chloride salt is treatedwith triethylamine to form the 2-[1-(methylthio)-1-(ethoxycarbonyl)ethyl] aniline. This ortho-substituted aniline was treated withhydrochloric acid to form 5.45 g (0.028 mol, 64% yield) of the3-methyl-3-methylthio-2-oxindole, m.p. 150°-151° (recr. from benzene);

ir (KBr) 3200 (NH) and 1680 cm.sup.⁻¹ (C=O); pmr (CDCl₃) τ 0.40 (1H, s,NH), 2.50-3.20 (4H, m, aromatic H), 8.10 (3H, s, SCH₃) and 8.31 (3H, s,CH₃).

Anal. Calcd for C₁₀ H₁₁ NOS: C, 62.15; H, 5.74; N, 7.25; S, 16.59.Found: C, 62.11; H, 5.70; N, 7.30; S, 16.57.

Desulfurization of the 3-methyl-3-methylthio-2-oxindole (1.5 g, 7.75mmol) gave a 70% yield of 3-methyl-2-oxindole, m.p. 122°-124° C. (Lit.,123°).

EXAMPLE 7 PREPARATION OF ETHYLα-(2-N-ACETAMINOPHENYL)-α-METHYLTHIOACETATE AND INTERMEDIATES THEREOF

Following the procedure described above aniline was converted to theN-chloroaniline, the N-chloroaniline was reacted with ethylmethylthioacetate to form the azasulfonium chloride salt, having generalformula IV. The azasulfonium chloride salt was treated withtriethylamine to form the 2-[(methylthio)(ethoxycarbonyl)methyl]aniline.

Instead of purifying the residue by column chromatography, it wasredissolved in 100 ml of dry ether and 20 ml of triethylamine. Whilestirring it at 0°, a solution of 3.4 g (0.044 mol) of freshly distilledacetyl chloride in 25 ml of dry ether was added to form the N-acetylderivative. After 2 additional hours of stirring, 50 ml of water wasadded and the organic layer was dried over anhydrous magnesium sulfate,filtered and evaporated. The residue was subjected to columnchromatography (silica gelmethylene chloride/ether) giving 7.07 g(0.0265 mol, 60%) of 21, m.p. 111°-114° (recr. from methanol); ir (KBr)3220 (NH), 1700 and 1640 cm.sup.⁻¹ (C=O); pmr (CDCl₃) τ 1.27 (1H, s,NH), 2.00-3.00 (4H, m, aromatic H), 5.34 (1H, s, CHS), 5.82 (2H, q,OCH₂), 7.83 (3H, s, CH₃), 7.98 (3H, s, SCH₃) and 8.79 (3H, t, CH₃).

Anal. Calcd for C₁₃ H₁₇ NO₃ S: C, 58.41; H, 6.41; N, 5.24; S, 11.99.Found: C, 58.24; H, 6.50; N, 5.23; S, 11.92.

This compound can also be named asN-acetyl-2-[(methyl-thio)(ethoxycarbonyl)methyl] aniline. It is usefulfor making 2-oxindoles by treatment with acid, as described above.

EXAMPLE 8 PREPARATION OF ETHYL α-(2-AMINOPHENYL)-α-METHYLTHIOACETATE,AND 2-OXINDOLE THEREFROM

Following the above-described procedure aniline was converted toN-chloroaniline. The N-chloroaniline was treated with ethylmethylthioacetate to form the azasulfonium salt and the azasulfoniumsalt was treated with triethylamaine to form 6.12 g (0.027 mol, 62%yield) of the ethyl α-(2-aminophenyl)-α-methylthioacetate, as a yellowoil. It can also be named 2-[(methylthio) (ethoxycarbonyl)methyl]aniline. It had the following analyses:

(undistilled) ir 3350 (NH₂) and 1700 cm.sup.⁻¹ (C=O); pmr (CCl₄) τ2.80-3.55 (5H, m, aromatic H), 5.48 (1H, s CHS), 5.85 (2H, q, OCH₂),6.02 (2H, s, NH₂), 8.05 (3H, s, SCH₃), 8.80 (3H, t, CH₃).

The compound is useful as an intermediate in preparing 2-oxindoles bytreatment with acid as described below.

Cyclization of ethyl α-(2-aminophenyl)-α-methylthioacetate to3-methylthio-2-oxindole was accomplished by stirring 2.00 g (8.9 mmol)of that acetate in 20 ml of ether for 4 hours with 10 ml of 2Nhydrochloric acid. The ethereal layer was dried over anhydrous sodiumsulfate, filtered and evaporated, giving 1.34 g. (7.5 mmol, 84%) of3-methylthio-2-oxindole, m.p. 126°-127° (recr. from ether); ir (KBr)1700 (C=O) and 3350 cm.sup.⁻¹ (NH); pmr (CCl₄) τ - 0.08 (1H, s, NH),2.70-3.20 (4H, m, aromatic H), 5.88 (1H, s, SCH), 7.84 (3H, s, SCH₃).

Anal. Calcd for C₉ H₉ NOS: C, 60.31; H, 5.06; N, 7.82; S, 17.89. Found:C, 60.16; H, 5.19; N, 7.71; S, 17.70.

Desulfurization of the 3-methylthio-2-oxindole (2.0 g, 0.011 mol) gavein 76% 2-oxindole as confirmed by comparison with an authentic sample.

EXAMPLE 9 PREPARATION OF 3-METHYLTHIO-2-OXINDOLE DIRECTLY FROM ANILINEAND ETHYL METHYLTHIOACETATE WITHOUT ISOLATION OF ETHYLα-(2-AMINOPHENYL)-α-METHYLTHIO-ACETATE

Following the procedure described above, aniline is converted toN-chloroaniline. The N-chloroaniline is treated with ethylmethylthioacetate to form the azasulfonium salt. The azasulfonium saltreaction mixture is treated with triethylamine to form the ethylα-(2-aminophenyl)-α-methylthio-acetate, and this orthosubstitutedaniline reaction mixture is treated with hydrochloric acid to obtain4.95 g (0.0276mol, 63% yield) of 3-methylthio-2-oxindole. This3-methylthio-2-oxindole can be reduced to 2-oxindole with Raney Nickelby procedures described above.

EXAMPLE 10 PREPARATION OF 2-OXINDOLE FROM ANILINE AND METHYLTHIOACETAMIDE

A. To a suitable reaction vessel containing 8.0 g (0.088 mol) of anilinein 250 ml of tetrahydrofuran (THF) at -70° there was added a solution of9.2 g (0.088 mol) of tert-butylhypochlorite in 15 ml of THF to form theN-chloroaniline. After 10 minutes a solution of 9.3 g (0.088 mol) ofmethylthioacetamide in 200 ml of THF was added quickly to preventcrystallization of the amide while maintaining the temperature below-40° to form the acetamidoanilino-methyl sulfonium chloride (V).

Almost instantaneously a precipitate was formed. Stirring was continuedfor 2 hours and after warming to room temperature the precipitate wascollected by filtration. Drying resulted in 18.10 g (0.078 mol, 89%) ofthe sulfonium chloride: dec. 107°-108°; ir (KBr) 1670 (C=O) cm.sup.⁻¹ ;pmr (DMSO-d₆) τ -0.57 (1H, s, NH), 1.70 and 2.20 (1H, s, NH₂), 2.30-3.10(5H, m, aryl H), 5.00 and and 5.20 (1H, d, J=16 Hz, ⁺ SCH₂) and 6.60(3H, s, ⁺ SCH₃).

An analytical sample was obtained by dissolving 0.5 g of the salt in 3ml of dimethyl sulfoxide and pouring it into 20 ml of THF. The solid wasfiltered and washed with THF.

Anal. Calcd for C₉ H₁₃ ClNOS: C, 46.45; H, 5.63; N, 12.04; S, 13.78; Cl,15.23. Found: C, 46.15; H, 5.65; N, 11.95; S, 13.86; Cl, 15.44.

B. To a stirred suspension of 4.0 g (0.0172 mol) of above sulfoniumchloride in 100 ml of methylene chloride there was added 2.3 g (0.021mol) of triethylamine and the mixture was stirred for 1 hour to form theα-(2-aminophenyl)-α-(methylthio)acetamide. This compound can also benamed as 2-[(methylthio)(aminocarbonyl)methyl] aniline. To the clearsolution there was added 25 ml of water, and after separation of layers,the organic layer was dried over anhydrous magnesium sulfate, filteredand evaporated to leave 2.83 g (0.0145 mol, 84% yield) ofα-(2-aminophenyl)-α-methylthio)acetamide as a solid residue, m.p.98.5°-99.5° C (recr. from chloroform);

ir 3250 (NH₂) and 1650 cm.sup.⁻¹ (C=O); pmr (CDCl₃) 2.70-3.90 (6H, m,NH2 and aryl H), 5.39 (1H, s, CHS), 5.66 (2H, s, NH₂), 7.88 (3H, s,SCH₃).

Anal. Calcd for C₉ H₁₂ N₂ OS: C, 55.08; H, 6.16; N, 14.27; S, 16.33.Found: C, 54.79; H, 6.19; N, 14.19; S, 16.30.

C. To a 1.70 g portion (0.0087 mol) of theα-(2-aminophenyl)-α-(methylthio)acetamide in 60 ml of ethanol, stirredfor 24 hours, there was added 1 ml of concentrated hydrochloric acid toeffect ring closure of the ortho-substituted aniline and to form3-methylthio-2-oxindole. The resulting solution was concentrated toabout 15 ml and poured into 75 ml of water. The precipitate wascollected by filtration and after drying there was obtained 1.22 g(0.0068 mol, 78% yield) of 3-methylthio-2-oxindole, m.p. 125°-127°.

D. The 3-methylthio-2-oxindole can be converted to 2-oxindole bytreatment with Raney Nickel as described above.

EXAMPLE 11 PREPARATION OF 5-CARBOETHOXY-7-METHYL-2-OXINDOLE ANDINTERMEDIATES THEREFOR

By the procedure described above, 4-ethoxycarbonyl-2-methylaniline wasconverted to the N-chloro-4-carboethoxy-2-methylaniline on a 0.015 molscale. The N-chloroaniline was treated with ethyl methylthioacetate toform the azasulfonium chloride salt, having general formula IV. Theazasulfonium chloride salt was treated with triethylamine to form the2-methyl-4-carboethoxy-6-[(methylthio)(ethoxycarbonyl)methyl] aniline.The resulting substituted aniline was treated with hydrochloric acid toform 2.45 g (66% yield) of5-ethoxycarbonyl-7-methyl-3-methylthio-2-oxindole, m.p. 195°-196° C.(recr. from methanol);

ir (KBr) 3350 (NH), 1700 and 1680 cm.sup.⁻¹ (C=O); pmr (CDCl₃) τ 0.12(1H, s, NH), 2.08 (2H, m, arylH), 5.58 (2H, q, OCH₂), 5.65 (1H, s, CHS),7.62 and 7.90 (3H, s, CH₃ and SCH₃), 8.59 (3H, t, CH₃).

Anal. Calcd for C₁₃ H₁₅ NO₃ S: C, 58.85; H, 5.70; N, 5.28; S, 12.08.Found: C, 58.84; H, 5.77; N, 5.17; S, 11.93.

An 0.80 g (3.01 mmol) portion of the5-ethoxycarbonyl-7-methyl-3-methylthio-2-oxindole in 130 ml of absoluteethanol was treated with Raney Nickel by the above described procedureto give 0.44 g (2.01 mmol, 67% yield) of5-ethoxycarbonyl-7-methyl-2-oxindole, m.p. 238°241°;

ir (KBr) 1700 and 1670 cm.sup.⁻¹ (C=O); pmr (DMSO-d₆)-0.50 (1H, s, NH),2.54 (2H, s, arylH), 5.83 (2H, q, J=6.0 Hz, (OCH₂), 6.52 (2H, s, CH₂),7.80 (3H, s, CH₃), 8.71 (3H, t, J=6.0 Hz, OCH₂ CH₃).

Anal. Calcd for C₁₂ H₁₃ NO₃ : C, 65.74; H, 5.98; N, 6.39. Found: C,65.71; H, 5.94; N, 6.43.

Additional compounds which can be prepared by the procedure describedabove include:

5-chloro-2-oxindole from N,4-dichloroaniline and ethylmethylthioacetate,

4,5-dibromo-2-oxindole from N,3,4-tribromoaniline and ethylmethylthioacetate,

5-cyano-2-oxindole from N-chloro-4-cyanoaniline and methylmethylthioacetate,

5-isopropyl-2-oxindole from N-chloro-4-isopropylaniline andα-methylthioacetamide,

5-ethoxy-3-methyl-2-oxindole from N-chloro-4-ethoxyaniline andα-ethylthiopropionamide,

5-propionoxy-2-oxindole from N-chloro-4-propionoxyaniline andα-benzylthioacetamide,

5-propyloxycarbonyl-3-methyl-2-oxindole fromN-chloro-4-propyloxycarbonylaniline and ethyl 2-methylthiopropionate,

5-phenoxycarbonyl-3-phenyl-2-oxindole fromN-chloro-4-phenoxycarbonylaniline and α-methylthio-α-phenylacetamide,

3-benzyl-2-oxindole from N-chloroaniline and2-methylthio-3-phenyl-propionamide, and the like.

I claim:
 1. A process which comprises reacting in an organic liquidsolvent which is sufficiently polar to dissolve at least a portion ofthe reactants under substantially anhydrous conditions at a temperatureof from about -78°C. to about 10°C. a compound of the formula:##SPC3##wherein R is hydrogen or a hydrocarbon radical free of aliphaticunsaturation containing from 1 to 8 carbon atoms; A is chlorine orbromine; each of Y and Z is hydrogen or a substituent which does notdonate electrons any more strongly than a meta methoxy group, and notmore than one of Y and Z, as a substituent, is ortho to the --N(R)Agroup position on the ring; the --N(R)A group position having at leastone ring carbon atom ortho thereto in an unsubstituted state; with aβ-thio carboxylic ester or amide having a formula selected from thegroup consisting of ##EQU1##wherein R¹ is lower alkyl, phenyl or benzyl;R² is hydrogen, lower alkyl, phenyl or benzyl; R³ is lower alkyl, phenylor benzyl; each R⁴ is hydrogen, lower alkyl, or the two R⁴ groups aretaken with the nitrogen to complete a ring containing from 4 to 5methylene carbon atoms and up to one ring oxygen atom; for a timesufficient to form an azasulfonium salt having a formula selected fromthe group consisting of ##EQU2##wherein Y, Z, R, R¹, R², R³, each R⁴ andA are as defined above, and at least one of the phenyl ring carbon atomsortho to the nitrogen is in the unsubstituted state.
 2. A process asdefined in claim 1 in which an azasulfonium salt of formula IV or V isreacted with a substantially anhydrous base to effect rearrangement ofthe azasulfonium salt and to form an amino compound having a formulaselected from the group consisting of ##STR6## wherein Y, Z, R, R¹, R²,R³, and R⁴ are defined in claim
 1. 3. A process as defined in claim 2wherein an amino compound of formula VI and VII is treated with an acidor heated to from about 50°C. to about 150°C. to form an oxindolecompound of the formula ##SPC4##wherein Y, Z, R, R¹ and R² are asdefined in claim
 1. 4. A process as defined in claim 3 wherein theoxindole compound of formula VIII is treated with a de-sulfurizingreducing agent to form a compound of the formula ##SPC5##wherein Y, Z,R, and R² are as defined in claim
 1. 5. A process as defined in claim 4wherein R is hydrogen, A is chlorine; each of Y and Z is selected fromthe group consisting of hydrogen and halogen, nitro, cyano, lower alkyl,lower alkyloxy, lower acyloxy, carbonyloxy-lower alkyl andcarbonyloxy-phenyl groups;the sulfur containing compound has formula IIwherein R¹ is lower alkyl, R² is hydrogen and R³ is lower alkyl to forma compound of the formula ##STR7##wherein Y, Z, R and R³ are as definedherein.
 6. A process as defined in claim 5 wherein anN-chloro-4-carboethoxyaniline is reacted with ethyl methylthioacetate toform the azasulfonium chloride, the resulting azasulfonium chloride isreacted with a tris (lower alkyl) amine, to form2-[(methylthio)(ethoxycarbonyl)methyl]-4-carboethoxyaniline, and theaniline is treated with an acid to form the3-methylthio-5-carboethoxy-2-oxindole.
 7. A process as defined in claim6 which further includes the step of treating the3-methylthio-5-carboethoxy-2-oxindole with a desulfurizing reducingagent to form 5-carboethoxy-2-oxindole.
 8. A process as defined in claim7 wherein the reducing agent is Raney Nickel.
 9. A process as defined inclaim 5 wherein an N-chloro-toluidine is reacted with ethylmethylthioacetate to form the azasulfonium chloride, the azasulfoniumchloride is treated with a tris (lower alkyl) amine to form a2-[(methylthio)(ethoxycarbonyl)methyl] toluidine, and the resultingtoluidine is treated with an acid to form a 3-methylthio-2-oxindole ofthe formula ##SPC6##
 10. A process as defined in claim 9 wherein the3-methylthio-2-oxindole is treated with a de-sulfurizing reducing agentto form an oxindole of the formula ##SPC7##
 11. A process as defined inclaim 10 wherein the de-sulfurizing reducing agent is Raney Nickel.